Tuesday, March 29, 2011

Admittedly, we have been laying in on pretty thick on the anti-doping these past couple of weeks, but with the news coming out of the cycling world it was, unfortunately, quite topical. Fortunately the marathon season is upon us! We are really looking forward to some great racing this year, because the last 2-3 years have seen the rise of several new and young talents that have debuted or run extremely fast times. Most of that class has not been able to replicate their initial success, but with all the majors starting next month you can be sure they are ready to prove to us all that they are not one-hit wonders.

Astute and observant readers might have noticed a subtle change on the site under the "Who are the sports scientists" section on the right column. Namely, my employment status has changed from the University of Illinois at Chicago to The Vitality Group. The departure was sudden, not planned in advance at all, and the process went very quickly, taking only about five weeks to finalize the details. Officially my first day in my new position---Director of Clinical Development---was Monday, 14 March, and I am happy to say I have hit the ground running and very excited about what lies ahead. It is actually an interesting story---both how the move came about and who is The Vitality Group, but we will spare you the soap opera for now and talk about the new company!

Who is "The Vitality Group," anyway?

Our South African readers will know Vitality well, because for the past 10+ years, the leading health insurance provider in that country, Discovery Health, has successfully bundled health and wellness with insurance. So much so, in fact, that well over one million members are enrolled in the program, which at its core provides meaningful incentives to individuals to make healthy lifestyle choices regarding diet, exercise, and screenings---"preventive medicine," so to speak. Vitality has been a huge success story in South Africa, allowing the concept to exported to the UK via PruHealth and to the USA via The Vitality Group, and even in China with Ping An, one of the largest insurance groups in that country.

I think we can all agree that as a population, we could exercise more and make better choices regarding nutrition. In fact people who are overweight, obese, or inactive will probably even admit to knowing that they should, in fact, make changes to their lifestyle, and they might even know that they are at higher risk for many things because of their inactivity or weight. Yet the story remains---as a population, at least here in the USA, we are overweight and inactive. The mean BMI is 27 (overweight) and the general population does not exercise. At all.

And I will not need to convince you of this one, either, but more active people who have a BMI below 25 spend less on medical care each year. So promoting health and exercise becomes a win-win: the insurer pays out less in claims, and the individual benefits from lower premiums as well as better quality of life as a result of engaging in healthier and more active behaviours.

The incentive: Part of human nature?

The evolutionary psychologists or perhaps the behavioural economists in the audience can debate why we respond to incentives, but the fact is we do. I recall a story from the Freakonomics movie, in which Steven Levitt talks about using an incentive program to toilet train their daughter. It worked, although the point about his story was that people learn how to beat the program! Which is why verification and sophistication are important parts of any rewards program that will reduce the amount of cheating, and therefore Vitality invests heavily in these characteristics of the program. But many scientists spend lots of time and money trying to figure out when incentives work best, why they work, and the magnitude of their effect, and as I learn this area of the scientific literature I will be writing more about the findings, because they are really quite fascinating.

So it seems a no-brainer to provide a reward for people to exercise and eat better, but no one has really done it on any scale that Discovery and Vitality has. The crux is that the rewards and incentive system must be "meaningful" and sophisticated. That is is a difficult nut to crack, which is probably why no one has executed it to the same level as Discovery and Vitality.

Translating science to application

One of the primary reasons we started this site nearly four years ago (attention shoppers, our birthday is 28 April!) was to apply science to the every-day athlete. One of our favourite quotes around here is, "Science without application is stamp collecting," and so we strive to translate the science and apply it to everything we are passionate about. And now I find myself at the very edge of application, even on the level of taking simple validated lab tools such as step tests to predict VO2max, and attempting to implement them in a meaningful and accurate way to tens of thousands of people.

Discovery Health has always been based solidly in actuarial science, and with the growth and expansion of Vitality they have added exercise and behavioural science. The really important questions around Vitality (now written on the white board in my office!) include, "How can we continue to innovate new ways to measure and verify activity, and not just how much someone did but how hard, and also how do we reward them based on the data we can collect?" These are key pieces of the puzzle as we try to make exercising and logging (verifying) those results as easy as possible so that the barriers to getting active and remaining active are as low as possible.

The journey continues

So it is happy trails to life in academics, which is an exciting thing because this new position is ripe with possibilities to engage in outstanding science. There are numerous questions we can ask about the role and efficacy of incentives in changing (health) behaviours. The area of :behavioural economomics" is key to this, and I am consuming many papers day by people in that field that are trying to understand how incentives produce action and can drive behaviour change.

This will also be an ongoing journey, because in science there are no absolute truths. The "truth," that final conclusion, is always a moving target as we develop new methods and design more elegant scientific models to explain what we observe. We cannot reduce anything down to one point, but the models we develop try to connect the many points that exist.

Saturday, March 26, 2011

Cricket is not a sport that we've done a great deal of analysis of here on The Science of Sport. The irony is that the very first post we ever did, way back in April 2007, was the day of Cricket World Cup Final, which is currently on again in India. That post, and maybe a few more on the marketing of the sport, represent the sum total of our cricket coverage (incidentally, cricket may be played seriously by only half a dozen countries, but it has one of the biggest player and fan bases of any sport, thanks to its huge popularity in India. So powerful is the Indian "force" behind the sport that I once heard that the second largest supporter base for cricket is in the USA...thanks to the all the Indian immigrants! Also, driven by the huge Indian market and its commercial clout, it is one of the wealthier and highest paying sports, at least for those fortunate enough to cash in on the 20-over format of the game)

South Africa - 5 out of 5, did they "choke"?

Cricket also gives us our lead-in to today's post, thanks to (yet another) South African failure to advance further in the 2011 World Cup. SA lost to New Zealand yesterday, bringing to five a run of "failures" in World Cups.

Those of you who follow the sport, and everyone in South Africa, will be well aware of South Africa's reputation as perennial chokers. Ever since the 1992 World Cup in Australia, South Africa have amplified the importance of the World Cup (on that occasion, it was rain that denied SA a chance), and every time, have fallen despite great expectations.

Part of the problem is that good performances between World Cups allow South Africans to build expectation to the point that we cannot possibly be beaten by another team unless we ourselves blow it! It is the "You can't beat us unless we beat ourselves" mentality. And the result is that when we don't succeed (and by success, you must understand we mean "win the whole tournament"), the post-mortem invariably falls on our 'choking' under pressure, because the underlying philosophy is that choking is when you lose games you should win (which, as we'll see, is not necessarily true).

Some of these failures have been agonizing for fans, most notably the failures of 1999, where dropped catches and run-outs against Australia only re-affirmed a growing perception that our cricketers were guaranteed to buckle under pressure.

"Choking" up in lights

The latest failure is bound to produce the same response. Everyone will speculate wildly on what happened in Bangladesh yesterday, and the "choker" tag will be up in lights here in SA. I know from my involvement with the SA Sevens team that such speculation almost always bears little resemblance to the truth. Knowing what is going on in a dressing room over 4 weeks of a tournament, and during 7 hours of a match is impossible, and wild speculation usually INCLUDES the truth without being it!

So rather than add to opinion, I thought it would be a good opportunity to look at what choking really is. The word is used so often that it's almost guaranteed to be misunderstood. Just yesterday, within minutes of the defeat to New Zealand, expert analysis said that we had "choked and panicked". The truth is that these two phenomena, both attributable to pressure, are polar opposites.

So let's take a look at what choking is, and how it differs from other failures under pressure.

"Choking" sounds like a vague and all-encompassing term, yet it describes a very specific kind of failure. Under conditions of stress..the explicit system sometimes takes over. That's what it means to choke. Panic, in this sense, is the opposite of choking. Choking is about thinking too much. Panic is about thinking too little. Choking is about loss of instinct. Panic is reversion to instinct. They may look the same, but they are worlds apart."

Sometimes the other team is just better (on the day)

So choking, a fascinating area of sports psychology and performance, is a very specific kind of failure, and to blame it for defeat (especially surprise defeat) is too convenient and easy to do. It's an overused explanation, and while there is almost certainly an element of both choking and panic in the latest defeat, team sports in particular are too complex for blanket explanations like choking.

The same focus will be on New Zealand later this year, when they host the 2011 Rugby World Cup. They too have been labeled as chokers because they are consistently the best team in the world, but have failed to win the knock-out games in the World Cup. Have they choked every time? Unlikely. Sometimes, it's just that the other team are better on the day, better able to raise their game when it matters.

As for the real explanation for defeats like South Africa's yesterday, only those involved can say, and they must be honest and hard to do find them successfully. If it was choking (and maybe it was, at least for some individuals on the team), then denying it doesn't help.

But it also doesn't help to blanket blame choking for defeat. The only exercise that is effective (again, this is in my experience from the SA Sevens setup) is that every single person must shoulder responsibility, ask themselves what they needed to do differently and then aim to address it. Were the best decisions made? Was the team prepared optimally? Were there problems for many months leading into the tournament that were glossed over deliberately, or ignored because it was inconvenient to confront them? Difficult questions, but lessons learned in failure are often the best ones. If you're prepared to learn them.

The cyclists, Rudi van Houts and Phillip Nielsen, failed tests last year, including the testing of B-samples, but were recently cleared of any wrongdoing, based on their defense that the drug entered their system as a result of contaminated meat. Both failed the tests after racing or training in Mexico (where, admittedly, it has been alleged that almost 20% of meat is treated and thus contaminated with clenbuterol).

These cases, most of you will already realize, are the same as that presented by Tour de France champion Alberto Contador, with the same outcome (for now).

We've written a fair amount on the Contador case already, but the most recent exonerations re-inforce the struggle that doping control has when a positive finding is not enforceable as a result of an explanation that can neither be proven nor disproven.

A difficult dilemma to solve - plausible explanation and "impossible" proof, both ways

The bottom line is that in terms of the implications for doping control, it actually doesn't even matter if the cyclists are guilty or not. Like Contador, they present an explanation that IS plausible. The problem is that neither party (cycling or the cyclist) can currently prove its argument.

Strict liability has always held that the athlete who has failed a doping control must explain how an illegal substance entered their system - the burden of proof lies with the athlete (but only once they've failed the test - this is an important distinction. It's not simply a case "guilty until proven innocent").

The Contador verdict effectively spun strict liability around 180 degrees, so that rightly or wrongly, it now seems to lie with the governing bodies to prove that the positive test was in fact the result of deliberate doping.

Proving the case - limits and hair samples

This seems impossible in cases like these. The only way to overcome this is to do detailed studies on the drugs to investigate levels expected in urine/blood/hair as a result of doping compared to contamination - both Contador and van Houts had incredibly small amounts in their bodies (50 and 30 pg/ml respectively, it's been reported). If one knew the amounts that occurred due to contamination, and if they were routinely this small, then it might be possible to classify clenbuterol as a "threshold" drug, which is allowed up to a certain limit, set by knowledge that doping produces a value of at least "X". That's currently not the case, and any clenbuterol is an adverse analytical finding, or "strike".

The problem with using the amount detected in the sample is that you never know the ingested (or doped) amount, and nor do you know the timing of ingestion (or use) relative to the test. These are clearly crucial as to what eventually gets detected, and without knowing this, setting thresholds is largely meaningless. And so the athletes will be cleared more and more, particularly as a result of the precedent created by the Contador case. This was one of the major implications of that verdict.

There is another option - a hair test. A German table tennis player, Dimitrij Ovtcharov, was exonerated after he provided a negative hair sample. Apparently, clenbuterol "sticks to hair" and so a negative hair test suggests contamination, since the drug would not be present in large enough amounts to remain in the hair. Strangely, this happens more with dark hair than blonde hair, so a light-haired person would produce a "vague" finding, according to one expert, Detlef Thieme. WADA are challenging Ovtcharov's exoneration, incidentally. Clearly, this is not yet a conclusive method of separating contamination from doping, but may be a prospect for the future.

Implications - reconsider clenbuterol

Clenbuterol therefore has three successive strikes next to its name - time to reclassify it on the list, or remove it altogether. Unless an alternative method of testing, or better understanding of the levels as a result of ingestion can be obtained, it seems to be unlikely that a positive test for this particular drug is NOT going to be challenged on the grounds of contamination.

And when that happens, it seems unlikely that a case can be resolved in favour of the authorities. So until such time that the authorities are able to disprove contamination, or prove deliberate doping, they are powerless to enforce test results. Time to retire clenbuterol, and save the athletes of having to present this argument and go through hearings that will ultimately produce a similar outcome.

The remaining alternative, and this is tongue in cheek, is that sports bodies will have to start insisting that athletes please submit a sample of all ingested meat for testing at every event! Urine in flask A, blood in vial B, and meat in container C, please...

Ross

P.S. The Contador case is of course not yet over - the UCI have until Thursday (with WADA getting an additional 3 weeks) to lodge an appeal against the Spanish verdict that cleared him. It may yet continue. But still, the possibility of contamination, and the fact that as yet, there seems no clear way to distinguish contamination from doping, means the longer the delay, the greater the problem for authorities.

Also, I'm unashamed to admit that on this particular topic, I can't even deliver satisfactory answers to many of your questions! It's clearly a mighty complex topic, and one that discussion will help grow understanding of.

So today, we forge ahead with what I ended off on, and that it is the question of whether the passport is worth the effort, or whether the cyclists are able to "dodge" it so effectively that it's just another attempt by the doping control to catch the dopers from behind.

The origin of this debate come from many sources. There is certainly a perception, or a swell of opinion, that because the passport sets such stringent limits, it "misses" or fails to detect when doping has occurred. People point to the lack of convictions as proof of its ineffectiveness. Hopefully, in that last post, I was able to explain or introduce why this very strict probability limit is applied. Before we can continue, I must recap very briefly (I won't repeat that mammoth post, don't panic!):

The Biological Passport concept in a flash

The passport concept is that regular measurements of certain blood variables, like the percentage of reticulocytes, hemoglobin, and a calculated score called the Off-score, can point towards blood doping

The principle is that it is possible to detect the effects of dopingwithout ever having to find the drug. To gather the evidence, so to speak, rather than having to find the smoking gun in the hand of the accused!

Each rider is measured throughout the season, and their values set what you might call "basal levels" because we know that when it comes to blood, there is only so much variability from one test to the next. That is, you don't go from a Hb concentration of 160 g/L to 190 g/L without suspicion.

So a trace of a rider's values that is developed longitudinally (over time) should NOT resemble a mountain range with huge peaks and valleys! The key point here is that each rider's values then set a range of probabilities for what a subsequent reading should be - the athlete is his own reference.

The key point, legally, is that because of biological variation that is NOT due to doping (pathologies, for example) and because of analytical errors (they do happen), there are multiple layers of security built in. They include:

A probability limit of 99.9% which means that a value outside of these boundaries (an upper and lower boundary) is correct 999 times out of 1000. Put differently, the chance of finding a "strike" or suspicious result in someone who is NOT doping is 1 in 1000 samples.

An expert panel who review the results from the ABP (Athlete's Biological Passport) software, and only initiate further discussion if multiple variables are over the limit

Once initiated, no case is opened until the expert panel requests an explanation from the athlete. If this is still deemed inadequate by the panel, then they go to an official enquiry. At this stage, a disciplinary procedure against the athlete could be initiated based on the presumption that a prohibited substance or method had been used - the cases of Pellizotti and Caucchioli represent CAS verdicts on this process, and they were positive

So that's it in a nutshell - the issue now is whether those "security levels" render the passport ineffective. Is it doomed to be another control that clever athletes dodge with ease or has it had an impact? For example, if the probability limit was set at 99%, then far more samples would be classified as "strikes". It would also mean a 1 in 100 chance of false positives, the downside.

I wrote last time that I feel the answer is that it very definitely HAS had an impact on the sport, and I'll describe why I believe that below...

An effective deterrent - the absence of convictions is not a symptom of ineffectiveness

Allow me an analogy. Say you have a stretch of road that is known to be a high accident zone as a result of speeding - guys hit 100 mph in the 70 mph zone. Authorities might decide to install cameras to catch people speeding. They might estimate that in a given week, an average of 500 cars speed through this section - it's impossible to know the precise number, because it can't be documented. Having installed cameras, they review the statistics and find that they are now catching 2 speeding cars per week. A failure? Are they looking in the wrong place? Not necessarily, for the obvious reason that as soon as drivers know that the risk has increased (provided they also believe that the punishment will be enforced if they offend, of course), they modify their behaviour accordingly.

This is an obvious and simple example that just because the passport is not catching doping cyclists, it may actually still be exerting an effect on the professional peloton as a result of what I would crudely describe as "fear" that this new system can catch dopers. Doping behaviour would thus be modified as a result of awareness, and the end result is that authorities might catch FEWER transgressors, but should still feel content that they're getting a problem under control.

Will people still speed? Of course. But will they speed less severely, and try to speed only when not being observed? Yes, and the end result is positive. Similarly, cyclists will dope, there is no doubt of this. But they will be more careful, and that has positive consequences.

Evidence of effectiveness - a fascinating graph

But, you are not going to just take my word for it (nor would I expect this!), so let's look for some evidence. If the cyclist is changing their behaviour in response to the increased chance they will be caught, then you can expect to see changes in the markers that reveal the EFFECTS of doping. In other words, you apply the Biological Passport concept, and investigate whether things are changing.

So here is a graph that gives me great confidence and hopefully some cause for optimism (thanks to Dr Mario Zorzoli via Prof Yorck Schumacher for steering me in the direction of this graph and allowing me to use it - the reference for the paper is at the end of the post for those who want it)

It shows the percentage of blood samples measured in professional cycling that had UNUSUAL reticulocyte percentages. You might recall from my last post that:

a LOW reticulocyte percentage indicates that there are fewer immature red blood cells because red blood cell production has been switched off - this happens after the infusion of RBC, or blood doping

a HIGH reticulocyte percentage indicates that there are more immature RBC, and this happens because of removal of blood or the use of EPO, which both stimulate RBC formation

a 'normal' or physiological range for reticulocyte percent is 0.5% to 1.5%. Anything outside these is suggestive of doping

Source: Zorzoli & Rossi, 2010; Zorzoli 2011

So, what are you looking at?

The green blocks show abnormal samples where reticulocyte percentage is HIGHER than normal - either 2 to 2.4% (light green) or above 2.4 to 5% (dark green). Remember that a higher reticulocyte % means more immature blood cells, suggesting EPO use or blood removal. So quite clearly, in 2001 and 2002, you had a high percentage of samples that suggest EPO use - between 9% and 11% of all samples, and 80 to 90% of suspicious samples. No surprise there.

Then comes the introduction of the urine test for EPO in 2002, which I've shown with a blue line. Suddenly, things change - now, you have much larger pink bars. The pink represents LOWER than normal reticulocyte percentage - either 0 to 0.2% (dark) or 0.2 to 0.4% (light)

So clearly, the EPO test changed things - from 2003 to 2007, between 6% and 10% of samples had low reticulocyte %, and these tests make up 80 to 90% of the abnormal test results. Remember, this suggests blood doping, and a shift in practice after the EPO test was introduced!

Introduction of the Passport and another change

Then comes the Biological Passport, shown by the red line in 2008 and a substantial drop in the total number of tests with abnormal reticulocyte %. This is clearly a good finding, because only 4% of all tests have unusual reticulocyte percentages, a drop from 14% in 2001. That's an enormous impact, and while it does not prove that doping is reduced, it does suggest that the Biological Passport has had a measurable and expected impact on the sport.

And there is the "elegant" timing where the introduction of a test first shifts the trend from high ret % (EPO use driving RBC formation) to low ret % (blood doping which suppresses RBC formation) and then seems to bring it right down. This strongly suggests that professional cycling has adjusted its behaviour in order to avoid detection, not once but twice - the first was a change, the second a reduction. The threat has therefore induced change. But there is more to this - it's linked to performance, and that's something I will pick up below.

But first, an important question. Does this prove that doping is not happening? Of course not - riders are smart, they micro-dose, they mask doping by using EPO to switch RBC formation back on when infusion would normally switch it off. There is still corruption, and no science, however powerful will be 100% effective if there is any hint of cover-up. Going back to my speeding analogy, people will always speed, but instead of hitting 100 miles an hour, they pull back to 80 miles an hour, and they "select" when to speed. Traffic officials will still accept bribes, officials will cover up some cases, but the overall trend would still be positive.

I would propose that a similar thing has happened for cycling. There is almost certainly doping, and I will remain a skeptic, but I'm also optimistic that this new method, which will continue to be developed and improved, is having an effect by forcing more caution, and smaller dosages.

That optimism comes in part from this graph, from testimonies within cycling (I honestly believe that cyclists are "nervous" of the science behind the Passport), and of course, performance, which I'll end off with now.

The performance decline in the Tour, and its link to doping control and the Passport

That all began with the hypothesis that the power output achievable without doping was limited and could be predicted based on physiology, and that any cyclist who went above this on a long finishing climb in the Tour was probably doing so with the benefit of doping! That "limit", I suggested, was about 6.2 W/kg, a climbing power output that was very common in the 1990s and early 2000s, but which has NOT been seen since about 2006.

The graphs below show the power output in the mountains, year by year. I haven't yet added the 2009 and 2010 figures, but it illustrates a point. And from our analysis in 2010, the highest power output achieved on a given mountain was ± 6W/kg, while the average is in the range of 5.7 W/kg to 6 W/kg. Much slower than preceding years.

The top graph shows average power output of the winner of the mountain stages, and the bottom shows the highest power output on a given mountain stage for the race winners. Again, read back to our discussion of the "limit" and you'll get a picture for how the sport is slowing down. It all builds a picture.

Wrap up

Eradicating it? No, not at all. And cases like those of Alberto Contador don't inspire confidence in the judicial process. Nor do riders like Ricardo Ricco, or Patrick Sinkewitz, or any number like them. The historical problems will not disappear overnight, particularly while many who were involved in creating the sport's doping culture either deny or continue to benefit from it.

But performance changes, and the initial results from the ABP do give cause for some optimism. Obviously, the novel methods must be further improved - if doping control stands still, it will fall behind, because the incentive to cheat (and find new, clever ways of cheating) exists. And you can be assured that this is happening - research to improve confidence limits, to tighten security and allow more certain limits to be set, to understand the physiology and pathology of blood values will help in future.

But for now, I hope I've given cause to suggest that the Biological Passport is not a failure by virtue of "catching" few riders. It's strength is in its longitudinal programme, and the science, and the fact that some smart people are tightening the boundaries.

Thoughts welcome!
Ross

P.S. As an addendum, the reference used for those ABP profiles in the post as well as the reticulocyte graph is as follows:

Implementation of the biological passport: The experience of the International Cycling Union. Drug Testing and Analysis, (www.drugtestinganalysis.com) DOI 10.1002/dta.173. Mario Zorzoli & Francesca Rossi. I might add that it's a great paper to read to find out about the ABP. It has details on how testing is done, quality-control, how many samples have been done and how they have impacted the sport. It's likely that a lot of questions will be sent to that paper for an answer!

And once again a huge thank you to Prof Yorck Olaf Schumacher, Prof Mario Zorzoli and also to Torben Potgiesser for their input. I don't know if any of you realized, but some of the comments in the discussion to the previous post were from them, and that is a rare privilege, to hear straight from those at the "front line" of the issue at hand. I am especially indebted to Prof Schumacher for steering me to publications on this topic.

They have therefore been banned not for failing dope tests or falling foul of criminal investigations (the other, seemingly more common way for cyclists to be 'caught' in this era of fallible testing). Rather, their ban is the first to be imposed based on the values measured in the biological passport system. One of the most significant aspects was that in the Pellizotti case, the UCI were appealing to CAS, who then overturned the decision by CONI (the Italian federation) to exonerate Pellizotti (in the Caucchioli case, incidentally, CONI banned the rider, and so Caucchioli was appealing to CAS. The verdicts give the passport some serious credibility.

In the words of the CAS summary: "the CAS Panel has reviewed in detail the biological passport program applied by the UCI and has found that the strict application of such program could be considered as a reliable means of detecting indirect doping methods."

What I will say, however, is that the case, and the resulting discussion, represents a great opportunity to discuss the science of the passport, and it's legal 'clout'. I've been very fortunate to have struck up a relationship with Prof Yorck Olaf Schumacher, one of the premier experts of the passport, and he has been very helpful in answering some of my questions and steering me in the direction of publications that help to explain the system.

So since the verdict, I've been working on pulling together some information that I hope helps to explain the passport a little more clearly, so that we can all understand its strength, the effect it has had on cycling, and also the limitations, because they will inspire future development to give it even more strength.

The Science: How does the passport system work?

About 18 months ago, we did an interview with Prof Schumacher, in which he explained the basic concept behind the biological passport. Here's an excerpt from that interview:

"In the biological passport, we try to identify suspect constellations of biological markers that can not be caused or explained by other means than doping. This applies to markers of the haematological system, but extends to endocrinology and other organs"

So what are these "suspect constellations of biological markers", and how does the legal "burden" affect the evaluation of the values measured? This is the fundamental starting point in understanding where the biological passport is headed as an anti-doping tool. So let's begin with some blood physiology.

Reticulocytes, blood doping and the off-score

The central "characters" in the biological passport story are reticulocytes and hemoglobin, which are combined statistically to produce an Off-score. Hemoglobin you know - the oxygen carrier, which picks O2 up in the lungs and delivers it to the tissues. Reticulocytes are immature red blood cells, which of course, carry hemoglobin. Their "life-span" before maturing is about one day, which means that at any moment, a certain percentage of your blood cells are reticulocytes, the rest are mature red blood cells. This percentage is important, as we shall see.

Both blood doping (the removal and re-infusion of red blood cells) and EPO use increase the oxygen carrying capacity of the blood in order to improve performance, and their use is the target of the biological passport.

"Normal" reticulocyte % is between 0.5% and 1.5%, but it can quite naturally lie outside this range. Also, the absolute level is by itself tells nothing about doping - the graph above shows this, because not once did this subject's reticulocyte % rise above 1.5%, yet he was blood doping for almost a year. I'll cover this crucial aspect in a little detail later.

After a withdrawal, the percentage of reticulocytes generally goes UP. This is because the body responds to the sudden loss of red blood cell content by stimulating more red blood formation. This means more new blood cells as a percentage of the total cell number, and is the whole point, because when you re-infuse that blood later, you get a double-benefit.

On the other hand, the re-infusion of blood (the blue arrows) causes a drop in reticulocytes. Why? Because the cells that are being re-infused are "older" (they've been stored in a refrigerator!) and so the new blood, post infusion, has more red blood cells, but fewer of them are immature.

The opposite is true for hemoglobin, incidentally. Here, the withdrawal of blood is characterized by a fall in Hb concentration, while the re-infusion of blood increases Hb levels acutely.

These two measurements, which are affected by blood doping and also EPO use (since EPO will stimulate red blood cell formation thus increasing reticulocyte %) provide nice "flags" for measurement. They are used to calculate what is called the "OFF-score", or "stimulation index", a ratio of hemoglobin to reticulocytes (the calculation, for those who are interested, is Hb x 10 - 60 (square root of the reticulocyte %)).

The Off-score is of interest because it would be able to pick up both withdrawal of blood (characterized by a rise in reticulocytes and a fall in Hb), as well as the re-infusion of blood (reticulocytes fall and Hb concentration rises).

As is the case with reticulocytes, there is a "normal" or undoped range in Off-scores that lies between 80 and about 110, but because of differences between individuals, natural variation and probabilities, it's not good enough just to set an upper limit and use it to ban cyclists. This is where the issue of probabilities and variation comes in - if you are going to enforce passport results to ban dopers, you need to be 99.9% sure that those measured values do not occur in an undoped athlete.

Probabilities and the legal considerations: False positives

The end result is that in order for the biological passport to stand up to forensic and legal scrutiny, one has to manage the risk of "false positives", cases where a cyclist is not doping but their blood values are flagged as "suspicious". The only ways to manage this are to:

Set confidence limits or boundaries that are safe and unlikely to produce many false "strikes". If you do this, and set a confidence limit of 99.9%, then you can define samples as suspicious or abnormal if they exceed the statistical individual threshold with a 99.9% probability.

Put differently, if you set the limit at 99.9%, then the chance of finding values outside this boundary from an undoped athlete is 1 in 1000 samples. Those are pretty good odds, and are in line with most legal precedents. If you lowered your probability level to 99%, then the chances of finding a value outside this is 1 in 100, without doping. Obviously, not quite as good.

Test and research what constitutes "normal", how much variation is acceptable without doping and to progressively tighten the boundaries or limits so that you can begin to say with confidence that a given change in blood markers indicates doping.

Return for a moment to that study by Pottgiesser that I mentioned earlier - this study simulated a 42-week cycling season and split a group of cyclists into a blood-doping group and a non-doping group. Just to highlight that "false positives" do happen, the following figure is taken from their results - it shows the reticulocyte, HB and Off-scores for a cyclist who is NOT doping. The darker line in the middle of each graph is the measured values, while the two lighter lines represent that confidence limit that I was talking about earlier. Here, it is set at 99%.

The key graph here is Hb on the top left - you will see that on the very first day, this cyclist would have been given a "strike" for a Hb value that lay outside the 99% limit. Every other value was fine, but that one, for whatever reason, lay above the threshold - clearly the threshold is "imperfect" (Just a note on the reason - it may be related to the fact that this is the first reading, and therefore, the boundaries are set for all subject with no previous values. Individuals who have naturally high levels may fall outside this range. The addition of more measurements however improves the probability limits)

For comparison's sake, here is the doped subject whose graph of reticulocytes I redrew earlier in the post:

This cyclist would have received three "strikes" during the season - one for Hb and two for the Off-score. All three, of course, are legitimate in this case.

The conclusion of this Pottgiesser paper, incidentally, is that the off-score had high sensitivity in detecting autologous blood transfusions - in 11 cyclists, it caught 8 during this simulated season at a probability level of 99%. At 99.9%, as you might expect from more stringent limits, it picked up 5 out of 11 doping athletes over the 'season'. The only false positive came from Hb in that one subject, not from the Off-score, which was recommended for future use in the biological passport model.

As I mentioned previously, this Off-score is attractive because it can pick up both withdrawal (reticulocyte % rises and Hb falls) and re-infusion (reticulocyte % falls and Hb rises) of blood. Just to emphasize and illustrate, here is the above doped subject's Off-score again. I've highlighted the two "strikes" with orange diamonds, where the measured values lie beyond the boundaries that are set by a 99% probability level (the lines shown in light blue). You can see how the Off-score picked up both the infusion (first strike) and the withdrawal (second strike):

The biological passport process - multiple stages

OK, so having established what the passport is measuring, and also that there is this probability issue, the next piece of the puzzle is the process. And given that the passport works on the balance of probabilities, this is how the system is set up to run.

About 800 samples form the collective exposed to the biological passport programme, and they are providing blood samples regularly - these samples are analysed as I explained above.

All measurements are analysed by a team of experts using software that is based on Bayesian statistics, and they calculate the probability of the values being found in a normal, undoped sample. As mentioned above, these limits are set at 99.9%, which means that by finding values beyond those boundaries will mean that such values are only found in one of 1000 cases in an undoped individual.

Just to illustrate a key point, if they set the limits at 99%, then in the cycling collective of 800, you'd expect 8 cases of "false positives" where the rider's value is flagged when there is no doping. This is why the limits have to be very strictly set in order to have legal "clout" - it's too easy to dismiss a method that produces this many false positives. The downside, of course, is that cyclists who are doping can still go undetected, but there is this compromise between "cavalier" testing with high risk of false positives and the desire to catch every doper. There are built-in steps to manage this, however.

Cases are usually opened only if several different variables are beyond these boundaries on more than one occasion. By this measure, our non-doping subject who was picked up in the research study I described earlier would not face investigation, which is how it should be.

When this happens, the experts get together to evaluate and analyze the values. If they feel that the profile is typical for a certain doping intervention, the athlete is contacted and questioned about potential reasons for his values. His justifications are again evaluated by the experts. Only if they are still convinced that the profile is typical of doping and is not caused by the explanations put forward by the athlete (as has happened for Pellizotti and co), do they suggest the opening of a procedure against the athlete.

Clearly, the process is quite long and has multiple "security" levels to protect the clean athlete or to filter out pathologies that might cause abnormal values.

The effectiveness of the passport - if we can't catch them all, is it worth it?

That's a quick overview of the biological passport - how it works, what it measures, and why it is not as simple as just setting a limit and banning everyone who exceeds it. Sometimes, you can dope but still remain within those limits, whereas other times, people who do not dope may exceed them!

So the key is understanding probabilities. Having hopefully done that, you may now be wondering whether the biological passport is even worth anything? Is it effective, given that the probability has to be so high, and there is this much physiological variation that we can "miss" dopers (even the Pottgiesser study caught 8 out of 11 - three fell through). I have read a great deal on the internet and there seems to be an opinion that if the biological passport cannot assure detection and conviction of doping, then it is ineffective and should not be bothered with.

That's a whole other debate. I want to say that the answer is a resounding "Yes, it is effective", and I have some pretty cool data to back up that I believe the biological passport is having a significant effect on doping in cycling. And I also want to discuss where it may be headed in the future.

But right now, this is a lot to take in (and even more to try to write!), so I'll leave it at this, and say join me soon for more on this topic!

Ross

P.S. Just to add, the kind of debate in this post (and the debate and questions it will create) is exactly what the CAS would consider as vital in hearings like those of the Italian cyclists. A cyclist going to the CAS is going to have to present their defense, and their most likely arguments will be that analytical or laboratory errors were made (procedural issues - see the CAS summary), or the possibility that the rider has some 'abnormality' that produces either high or low Off-scores without doping.

So the officials evaluating cases like this are going to be asking questions like "How likely is it that a cyclist can produce an Off-score outside the 99.9% probability limit if they are not doping?", and "What kind of conditions would explain the biological profiles that we're being presented with?"

To explain the CAS process a little, what happens is that when a case is presented to CAS, a panel consisting of three judges is put together. Judges come from a pool of people who work for CAS, and one is proposed by each party, with a third neutral judge making up the three-person panel. These three are judges, not scientists, and so you can appreciate how a case like this presents to them some pretty serious challenges. When it comes to expertise, CAS has the choice: Usually, they will listen to the experts of either side and then come to a judgment. In some cases, they will bring in neutral experts who can explain and translate what is often very complex science in order to help them reach the right verdict. The same would have happened in the Oscar Pistorius case, incidentally, but as far as I know, they did not opt for a neutral expert in either case.

As a result, the studies like those of Pottgiesser become incredibly important. The reality here is that we are entering unchartered waters, and the more data the better, for the arguments of those wishing to use the passport as a tool.

Monday, March 14, 2011

Pacing, the governor and the athlete's clock: A brief interview on a fascinating concept

Jonathan came across the video below earlier today. Now, I must confess that I had never heard of the speaker, a Dr Thomas Rowland. Nor have I had the opportunity to read the book about which he speaks in this interview, called "The Athlete's Clock". But the concept grabbed my attention immediately, because as you may know, this whole aspect of the brain and the regulation of exercise performance was the subject for which I obtained my PhD.

So naturally, when the very first seconds of an interview present the question "Briefly describe the Central Governor theory and where you are in adhering to it?", my curiosity is raised. And pleasantly, I have to say that the admittedly short summary that Rowland provides about it is a pretty good version of what has been developed and proposed (by Prof Tim Noakes, and all those who have developed this theory over the last decade or so, including, in my PhD and its research, me!).

Here's the interview, with more comments below:

In a nutshell

What Rowland describes accurately is that your ability to pace yourself during exercise is the result of an "anticipatory calculation" that is made by the brain during a race/training session, and whose purpose is to prevent you from causing physiological damage to your body.

He talks about how the brain prevents you from "over-exerting" (± 40 sec in the clip) and controls the pace you can select in order to do this. He goes on to talk about these "dangers", and mentions the examples of "breaking bones", "shredding muscles" and causing a lack of coronary blood flow to the heart, all of which are possible but never occur.

Here's where it's a little more complex than the interview allows for (understandably), and what Rowland has not mentioned is maybe the most obvious and clear-cut illustration of how pace must be regulated to protect physiology, and that is during exercise in the heat. When we exercise in hot conditions, our pace is regulated very early on in order to reduce the rate of heat storage. Why? Because if we didn't slow down, we'd soon be the "victims" of a potentially harmful rise in our core temperatures. There's quite a lot of evidence that beyond about 40 degrees celsius (maybe 41 in a highly motivated athlete), exercise is basically impossible and we lose cognitive and motor function. Above 41 degrees, things get risky - heat stroke and the eventual risk of death are a good reason to stay below this threshold!

But happily, that rarely happens, because our brain, and this "governor", is in control and it reduces our level of muscle activation in order to prevent us from achieving these rates of heat storage and high body temperature. Quite literally, your brain does not allow you to activate the same amount of muscle, and thus forces you to slow down. The end result is that we slow down BEFORE becoming too hot, and not because of it.

That this happens is intuitively obvious, but was never really allowed for in studies where athletes were made to exercise to exhaustion - that kind of model gave us the theory that we "fail" at a certain point (high temperature, in this case). And while this is true, it is incomplete, because during self-paced exercise, which is pretty much 99% of what we do, we have this option to slow down. How this is achieved is a fascinating physiological question.

True in every situation

The same is true in every situation - at altitude, it's not the body temperature or rate of heat storage, but the degree of oxygenation (perhaps to the brain, according to latest work) that is regulated. In other situations, energy supply, blood glucose and glycogen levels are defended. In others, plasma osmolality - there are innumerable different "homeostats", all of which are monitored and regulated by the brain, and then controlled by changes in exercise intensity. And that, in a nutshell, is the Central Governor theory.

A contentious theory

Of course, no theory fits into a nutshell, and there's a lot more to it than this, including some contentious issues. Perhaps the most common one is that the "central governor" is not a distinct location - there is no little "black box" in the brain that is doing this calculation. It is a concept, and therefore, allows for multiple areas to regulate performance.

This too is actually obvious, because if you think about it, in order for the brain to monitor the physiological status of so many different systems must mean it is done in multiple systems or brain areas too. So afferent (or sensory) information must be interpreted in many different areas of the brain, each with its own function (like the anterior hypothalamus for increasing temperature, for example), and these different areas all produce this conceptual response.

There was even a time, during the period when I actually wrote my PhD thesis in 2005/6, where we tried to move away from this term "central governor", because so many people seemed to miss the point that it was not a distinct location or brain structure that had not yet been discovered. Rather it was the function, during exercise, of existing areas, which performed the role described by Rowland in the interview above. However, people failed to appreciate this, mostly, I suspect, because many stopped reading the early work of Prof Noakes because it "offended" their paradigm.

The result was that the theory evolved steadily, but the knowledge of what was being proposed did not, at least among those who were opposed to it. I remember attending conferences in the USA and Europe as a young PhD student in 2004 and 2005, and feeling enormous frustration that those who argued loudest seemed often to be the ones who had stopped reading in about 1999, and were therefore pouring enormous energy into criticizing concepts that had evolved by six years while they were looking behind them.

It was as if they expected a theory to be complete in its first iteration - that version 1.0 would be the final one, no improvements allowed (of course, if this were true in other areas, can you imagine what cell phones would look like?). Had they spent time and energy reading the latest research, I dare say many would have agreed with much of it. This sadly will never change, but happily, new researchers are debating the issue rather than its ancestors (and their ancestors, in this case...). Interestingly, those who argued loudest early on have still failed to acknowledge the research, but are now producing papers were they are effectively claiming "We knew the brain was involved all along" - this is typical of the evolution of knowledge. More on this in a future post...

Conscious vs unconscious, and the rating of perceived exertion

Another fascinating area of the debate is whether this regulation is "unconscious" or not. Do we make a conscious decision to slow down, based on cognitive processes and experience, or does the physiological process happen unconsciously, with us becoming aware of it later? That's open to debate, but my feeling was always that it was unconscious - it had to be, because conscious motivation can be as high as you want, but if you overheat/run out of glucose/become hypoxic, you slow down.

Also, athletes slow down with the same perception of effort, which said to me that something in the brain was upregulating their degree of discomfort even while reducing their muscle activation and pace. If a conscious decision was responsible, you'd see a rise in RPE either before they slowed down (in which case the RPE would be the cause - a conscious model), or you would see a fall in RPE afterwards (if RPE was the effect of a conscious decision). The fact that it is neither, I reckon, says that the RPE is part of the regulation, which is therefore unconscious. This is somewhat philosophical, of course.

Then related to this is the issue of "failed" pacing strategies. What happens when athletes get it wrong, and go out too hard, and do actually overheat early? What happens in sprinters who tie up before the finish line? I'm actually embarking on some studies to look at this question right now, using cerebral palsy as a model.

In the end, I proposed (in my PhD) a model where the subjective rating of perception of exertion (RPE) was the "integrator" of all these different physiological cues. Your RPE is the means by which all these different brain regions integrate those multiple signals - how hot you are, how much oxygen the tissues and brain have, how much energy is available, the mechanical strain on tendons, ligaments and muscles, and so on.

The RPE then plays the crucial "fulcrum" role, because it is generated as a result of the sensory inputs to the brain, but is also a mediator of the reduction in muscle activation and pace, specifically to make sure that the RPE does not exceed an acceptable level - after all, the reason you slowed down in your last 10km was because you felt terrible at the pace you were running! What was happening physiologically was responsible for this, and it changed thanks to your brain slowing you down, but you didn't know that status at the time!

For those wishing to read more, I hate to reference myself, but it seems the most distinct place to start from to learn about about pacing, and these are the two reviews of the literature that arose out of the PhD:

As for the book Rowland has written, "The Athlete's Clock", I can't vouch for the rest of it. Hopefully, I will grab a copy at some stage, and then I can post properly on it! But it's great to see a book reaching a wider audience on this topic (but then I'm biased!). It also makes me think I should have written this book first!

Upcoming attractions

So I confess that this was supposed to a short "filler" post, just to keep the fire burning until the next big post. I guess doing a "short filler" post on a topic as large as this, especially one to which I devoted years of research, was always impossible! Apologies!

When that next post comes (hopefully later this week), it will be on the biological passport, which received a huge boost recently when the Court of Arbitration for Sport (CAS) ruled in favour of the passport by suspending two riders for "suspicious blood values".

The bio-passport has come under fire lately, because of what is perceived to be an inability to catch riders who cheat using all kinds of clever methods like micro-dosing and masking. I think it's important to keep in mind that it's early days, and that researchers are slowly developing the tool. I believe it has already had enormous positive effects on the sport, and I'll explain some of its limitations and why they don't necessarily destroy its value.

So I'll look at this in more detail, combined with some great inside information on the passport from one of its experts, and where it might be headed, as well as some of the legal issues it may face.

Also, stay tuned for some exciting news from Jonathan's life, and what it may mean for us here at The Science of Sport!

Wednesday, March 09, 2011

Data visualization continued: The beauty of statistics (not an oxymoron)

As a continuation of my last post on the presentation of data, and how essential it is to communicate science to a larger population outside the "constraints" of scientific journals alone, here are a few videos and a website that the data-fiends among you will love! It also buys me some time, since I'm rather snowed under with work at the moment!

Last time, I introduced David McCandless, a designer who runs a great site called Information is Beautiful. Below is a video of his TED Talk, where he presents some of his data visualizations. Good to watch!

Then second, and a presentation that more than a few of you sent me, is a TED Talk by Hans Rosling, a medical doctor who is Professor of International Health at Karolinska Institute in Sweden. His talk, using software developed to show statistical trends in the world's population economics and demographics, is one of the great achievements in data presentation (that I have seen anyway).

I was going to post this clip last time, but I didn't want to go overboard, but it's a great addition to the examples of excellent data visualization.

And for more of the same, visit Hans Rosling's website, GapMinder. Whether or not you are interested in the actual content (statistics and trends of everything ranging from CO2 emissions to HIV prevalance), the way in which the data is shared, managed and then presented is mind-blowing.

Of course, not everyone has such powerful software, and so you may be thinking this is all good and well, but beyond your capacity without the technology. Which is understandable, but I would stress that the ability to simplify and present complex ideas in a simple, accurate and easy to follow manner is more about thought process and the discipline of translating data, with the software being the front end and nice to have, but not essential. The goal is to have the ability to present the idea using a pencil and paper if that's what you have available!

Jonathan Dugas, PhDCurrent residence:Chicago, USAEmployment: Director of Clinical Development, The Vitality GroupResearch interests: Temperature regulation and exercise performance, with a special emphasis on how fluid ingestion affects those two things. In addition, the effects of exercise on health improvement and risk modification in large populationsSports interests: Cycling, running, triathlon, endurance sports

Full discolusre:The views expressed on this site are not those of the University of Cape Town (UCT), the Sports Science Institute of SA (SSISA), The Vitality Group, or Discovery Holdings.